Systemic lupus erythematosus (SLE) is characterized by high titer IgG autoantibodies to ubiquitous intracellular components. Several inbred mouse strains also develop spontaneous lupus, with the same spectrum of autoantibodies. Autoantibodies in lupus appear to arise as a consequence of autoantigen-specific alphabeta CD4+ T cell help. Autoreactive T cells in lupus presumably bypass normal tolerance mechanisms, although mechanisms of tolerance escape for T cells responsive to ubiquitous self peptides are unknown. This proposal will address the hypothesis that lupus T cells have intrinsic (genetic) defects that render them more susceptible to activation through their T cell receptor (TCR)-CD3 complex after contact with self- peptides, a defect that contributes to tolerance loss with expansion of autoreactive, peripheral T cells. This hypothesis is based in part upon preliminary data indicating that naive, mature T cells from Fas (CD95)-intact, lupus-prone MRL (MRL/+Fas- lpr) mice are hyper-proliferative after TCR stimulation, compared to T cells from non-autoimmune mice. Indeed, the former cells are hyper-proliferative after contact with peptides having low affinity for the TCR, as determined in studies using TCR receptor transgenic MRL and control mice. To further address the hypothesis, three specific aims are planned. First, differences in in vitro activation and survival between T cells from Fas- intact MRL and non-autoimmune mice will be sought. Here, T cells from wild type and from TCR transgenic animals will be analyzed for activation, IL-2 production, death, and TCR signaling events after stimulation with anti-CD3 and with cognate and variant peptides, including those with low affinity for the transgenic TCR. Second, differences in in vivo activation and survival between MRL and control T cells will be sought via immunization or tolerance induction with cognate or variant PCC peptides. Finally, it will be determined if these differences in T cell activation phenotypes are associated with a candidate locus from the MRL genetic background. Here, activation phenotypes will be compared using T cells from non-autoimmune B6 mice and B6 mice congenic for a candidate MRL locus on chromosome 7 that may be associated with an intrinsic T cell abnormality.